New Study Examines the Inner Working of the FDA's Approval Process

Often regarded as one of the most powerful regulatory agencies in the world, the U.S. Food and Drug Administration (FDA) can affect the lives of billions with its decisions. For decades earning the approval of the FDA meant that a product has undergone a multitude of rigorous and well controlled investigations and demonstrated itself safe and effective for public consumption. Some people have wondered if the FDA has more recently allowed its strict sense of protocol to give way to more malleable practices.

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  • A recent investigation published Jan. 21 in the Journal of the American Medical Association  (JAMA) led by Nicholas Downing, AB, Yale University School of Medicine, sought to investigate whether current approval standards, that may seem more lenient, lead to some therapeutic agents being approved by the FDA on the basis of thoroughly designed clinical trials while others are approved on the basis of fewer or less robust studies and thus may alter the perceived level of certainty about the risks and benefits of newly approved drugs.

    The authors evaluated the strength of the clinical trial evidence supporting FDA approval decisions for novel therapeutic agents — pharmacologics and biologics — between 2005 and 2012, characterizing key features of pivotal efficacy trials such as size, design, duration, and end points. Results showed that within the seven year period the FDA approved 188 novel therapeutic agents for 206 indications on the basis of 448 pivotal efficacy trials. Despite the FDA requirement for evidence from a minimum of two randomized clinical trials supporting an effect on health outcomes, 37 percent of product approvals were on the basis of a single pivotal trial.

    Though not required as part of FDA approval, any comparative effectiveness information was available for less than half of indications, leaving evident uncertainty about the benefits and safety of these medications when compared with other available therapeutic agents. Additionally, trials using surrogate end points as their primary outcome formed the exclusive basis of approval for nearly half of the indications in the study. Lastly, the data found that the majority of trials evaluating therapeutic agents indicated for chronic treatment lasted less than a year, raising questions about the certainty of the medications' long-term efficacy and safety.

    "We studied eight years of FDA approvals and found that the evidence required for approval varied substantially," said Harlan Krumholz, MD, SM, FACC, co-author of the study. "More than one third of the drugs were approved with only one clinical trial. About half of the studies were approved based on evidence related to surrogate markers rather than patient outcomes. And only 40 percent had evidence that compared the drug under consideration with existing therapies."

    Despite their consternation of the FDA's varied standard of evaluation, the authors of the study acknowledge that its regulatory flexibility does have some advantages, particularly when it comes to rapidly approving potentially effective therapies for life-threatening diseases such as certain cancers or diseases for which there is no existing effective treatment. Krumholz adds that "The flexibility in approval may serve society well, but there is a need for patients and doctors to know about this variability when making decisions. And for those drugs with weaker evidence at approval, post-approval monitoring is particularly important."

    Moving forward, Downing and his team ultimately concluded that because comprehensive safety evaluations are difficult to undertake as part of randomized controlled trials, they believe the best course of action is to adopt a "life-cycle" approach for an improved understanding of drug safety and effectiveness. Such an approach would require continual collected data on the benefits and safety of therapeutic agents, as well as robust post-market surveillance that allows reassessments of drug efficacy and safety after market introduction.

    In a separate study also published Jan. 21 in JAMA, Leonard Sacks, MD, Office of Medical Policy, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, led an investigation into why FDA marketing approval for new drugs was either delayed or denied. Analyzing various memos and material previously inaccessible to anyone outside the FDA, the authors found that the FDA's criteria for approval is based on a multitude of factors including evidence of proper manufacturing, appropriate dosing, generalizable trial populations, adequate sample size, meaningful health outcomes and degree of influence on those outcomes, consistency among multiple end points and among different trials and sites, improvement over the standard of care, and evidence that benefits exceed harms.

    Meanwhile, in a separate article published Jan. 21 in JAMA, Benjamin Rome, BA, Harvard Medical School, led an examination into the FDA's regulation of high-risk medical devices and their premarket approval process (PMA). As a result of the 2004 Medical Devices User Fee Act, which holds the FDA to require the "least burdensome route" to approval, less than one percent of medical devices are approved through the PMA process. Other moderate and low-risk devices are routed through the 510(k) pathway, which allows devices to be marketed simply by the fact they show "substantial equivalence" to existing devices. Focusing on data from cardiac implantable electronic devices from 1979-2012, Rome and his researches provide insight into an underutilized third method: the "supplement" process. Finding that 5,925 supplemental PMA applications were processed for 77 original devices during that time period, Rome and his co-authors concluded that supplemental PMA applications are commonly approved without clinical testing, but based on reviewer judgments. According to the authors, while the main role of preclinical testing is to identify devices that demonstrate problems in the laboratory setting and thus avoid clinical testing of said device change, the absence of problems in the laboratory setting may not reliably predict the long-term functionality of the device in the human body where environment and physiologic forces make it impossible to replicate in the lab. "In making decisions about use of these high-risk devices, clinicians and patients should consider the strengths and limitations of the PMA supplement approval processes," note the authors.

    An editorial comment by Steven N. Goodman, MD, MHS, PhD and Rita F. Redberg, MD, MSc, FACC, notes, "Although these reports represent important steps in improving understanding of FDA decision making, further commitment to and progress toward ensuring transparency, including reducing report redactions, is needed to help the scientific community and other interested parties answer the questions these studies raise, thereby helping the FDA in its mission to find the right balance between allowing innovation and protecting the public's health."

    "As part of its new Strategic Plan, the College is committed to working with the FDA as new, transformational scientific technologies and therapies continue to emerge," said John Gordon Harold, MD, MACC. "Supporting members in the appropriate use of new drugs, devices and treatments at the earliest stages of development is key to ensuring the 'Triple Aim' of better outcomes, better care and lower costs."

    Keywords: Judgment, Drug Approval, Consumer Product Safety, United States Food and Drug Administration, Decision Making, Pharmaceutical Preparations, Perception, Standard of Care, Risk Assessment, Drug Evaluation

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